Genes often are differentially expressed during the development of an organism, and in particular cells in an organism. Understanding and manipulating an organism's temporal and spatial gene expression profile can be useful for developing new and improved biological products and therapies. Among the array of regulatory mechanisms that affect the gene expression profile of an organism, chromatin remodeling has an important role.
Eukaryotic DNA is tightly packaged into chromatin. The most basic element of DNA packaging is the nucleosome, which consists of an octamer of histone proteins wrapped by about 146 nucleotide base pairs. The compaction of eukaryotic DNA into nucleosomes and the formation of nucleosome arrays present natural barriers to genetic regulatory proteins, and to enzymes that interact with DNA. Chromatin-associated protein complexes reportedly can, among other things, stabilize and destabilize nucleosomal DNA and thereby affect nuclear processes that use DNA as a substrate (e.g., transcription, replication, DNA repair, and DNA organization) as well as regulators of these processes.
Some chromatin-associated protein complexes are reported to use the energy of ATP hydrolysis to increase histone mobility, and to thereby change the accessibility of certain nucleosomal DNA to enzymes that process genetic information and to genetic regulatory proteins. It is thought that ATP-dependent chromatin-remodeling protein complexes can have a role in both gene activation and repression. Researchers have reported the existence of ATP-dependent chromatin-remodeling protein complexes in organisms including yeast (e.g., SWI/SNF, RSC, ISW1, ISW2, and Ino 80), Drosophila (e.g., dSWI/SNF, ACF, CHRAC, and NURF), and human (e.g., hSWI/SNF, NuRD, RSF, and ACF).
Other chromatin-associated protein complexes are reported to change chromatin structure by covalently modifying histones (e.g., by adding or removing acetyl, methyl, phosphate or ubiquitin). It is thought that by covalently modifying histones, these protein complexes can affect chromatin structure and thereby change the accessibility of nucleosomal DNA to enzymes that process genetic information and to genetic regulatory proteins. Some of these histone-modifying protein complexes also are thought to affect the activity of ATP-dependent chromatin-remodeling complexes.
For example, some histone-modifying chromatin-associated protein complexes reportedly contain a polypeptide subunit having histone acetyltransferase (“HAT”) enzymatic activity. Such protein complexes are, in general, thought to have a role in activating transcription. Researchers have reported the existence of polypeptides having HAT enzymatic activity in organisms including yeast, Tetrahymena, and humans.
As another example, some histone-modifying chromatin-associated protein complexes reportedly contain a polypeptide subunit having histone deacetylase (“HDAC”) enzymatic activity. Such protein complexes are, in general, thought to have a role in repressing transcription. Researchers have reported the existence of polypeptides having HDAC enzymatic activity in organisms including yeast, C. elegans, Drosophila, Xenopus, chicken, mouse, human and maize.